Osteoarthritis (OA) is the most common degenerative disease of the joint and is the major cause of disability among people over 65 in the US. OA affects approximately 27 million Americans, and the annual financial burden of OA is more than $80 billion in the US. Medical therapies have been limited to pain relief, physical therapy, and joint replacement for end stage disease. There is a significant need for therapies to prevent OA progression and/or to reverse established disease. The progression of OA involves complex pathophysiological changes in the joint such as loss of articular cartilage, intra-articula inflammation, and subchondral bone sclerosis, suggesting that OA is not a simple cartilage disease but rather a disease of the whole joint as an organ. This conceptual shift of OA pathophysiology suggests that OA progression can be mediated by the crosstalk between joint tissues, but the molecular and cellular identity of the crosstalk remains to be elucidated. The overarching goal of this research is to define WNT1 as a novel signaling molecule mediating the crosstalk between articular cartilage and subchondral bone during OA progression and to evaluate mTORC1 signaling as a downstream mediator of WNT1 function in OA progression. The central hypothesis of this project is that induced WNT1 expression in subchondral osteocytes is involved in the pathophysiology of OA through the regulation of articular chondrocytes and subchondral osteoblasts and that mTORC1 signaling mediates the function of WNT1 in OA pathophysiology. To test this hypothesis, this project will utilize multiple genetic mouse models. The goal of Specific Aim 1 is to determine the function of WNT1 in the pathophysiology of OA. The goal of Specific Aim 2 will identify mTORC1 as a significant mediator of WNT1 function in the pathophysiology of OA. The significance of this study will be not only to determine novel molecular and cellular crosstalk as a pathophysiological mechanism of OA, but also to identify a specific signaling cascade contributing to OA progression. Therefore, the outcome of the study will provide new insight for the development of therapeutic strategies for OA treatment, especially for therapeutics that significantly inhibit OA progression. The Baylor College of Medicine possesses exceptional facilities for proposed work and the Department of Molecular and Human Genetics is committed to providing the best training for the applicant. Accomplishing this research will also provide sufficient training for critical skillsetsand in-depth knowledge for OA research, and will allow applicant to become a successful independent investigator focusing on the pathophysiological mechanism underlying OA.